Osteoclasts are the principal bone-resorbing cells, and their activity has a profound impact on skeletal health. Disorders of skeletal insufficiency, such as osteoporosis, are typically characterized by enhanced osteoclastic bone resorption relative to bone formation. A more complete understanding of the mechanisms by which osteoclasts differentiate from their precursors and degrade the skeleton is therefore critical to developing therapies for these often-debilitating diseases. Recent evidence showed that Regulator of G-protein signaling (RGS) proteins, play an important part in the regulation of Ca 2+ oscillations. RGS12 gene is a large regulator of G protein, having multiple functional modules, such as PDZ, PTB (phosphor-tyrosine binding), Rap binding domains and GoLoCo domain. RGS12 is capable of direct interactions through its PTB domain with the tyrosine-phosphorylated calcium channel in culture of primary dorsal root ganglion neurons. We have found that mouse RGS12 gene was predominately expressed in RANKL-induced osteoclast like cells (OLCs). Knockdown of RGS12 expression using RNA interference (RNAi) inhibited Ca 2+ oscillations and osteoclast terminal differentiation induced by RANKL in vitro. Nevertheless, there is no in vivo evidence for a general requirement for RGS12 signaling in osteoclast differentiation and bone resorption. Based on our preliminary data and the nature of RGS12, we hypothesized that RGS12 plays an essential role in osteoclast gene expression, osteoclast differentiation and activation through the regulation of Ca2+ oscillations and interaction with calcium channel. To test this hypothesis, we propose two specific aims. In aim 1, to generate RGS12 null allele to study the role of RGS12 in bone resorption using knockout technology. In aim 2, using RGS12 knockout model to define the function of RGS12 in regulating Ca2+ signal in osteoclast, in osteoclast gene expression regulation, and in osteoclast differentiation and activation so as to apply this knowledge to develop new diagnostics and therapeutics for human diseases of bone, especially for osteoporosis [unreadable] [unreadable]